The present invention relates to the quantitative determination of optically active substances in specimens and, more particularly, to apparatus and methods for non-invasively determining the concentration of optically active substances.
In a number of diseases, it is desirable to monitor levels of chemical agents in the organs of patients in order to control their medication. In processes for manufacture of biogenetic materials, it is desirable to monitor chemical agents in the reactor to determine the progress of the reaction. In either instance, monitoring of the agent without invasion of the medium is desirable.
Diabetes mellitus is a chronic systemic disease characterized by disorders in both the metabolism of insulin, carbohydrate, fat and protein and the structure and function of blood vessels. Diabetes can result in circulatory problems which may lead to kidney failure, heart disease, gangrene and blindness. A major unanswered question in diabetes therapy is whether improved blood glucose control will alleviate the long-term complications of this disease.
Normoglycemia is difficult to achieve in diabetics because insulin injections do not adequately mimic non-diabetic insulin secretion patterns since there is no feedback control of insulin delivery rate according to the prevailing glucose level. In the last few years, there has been an intensive effort to improve metabolic control in diabetics by developing more physiological strategies of insulin administration. Three important approaches are (a) self-monitoring of blood glucose samples and adjustment of insulin dosages based on the results, (b) electromechanical devices for infusion of insulin and (c) transplantation of the pancreas or islets of Langerhans.
As is known, glucose is the main circulating carbohydrate in the body. In normal individuals, the concentration of glucose in blood is tightly regulated, usually in the range between 80 and 120 mg/100 ml, during the first hour or so following a meal. The hormone insulin, normally produced by the pancreas' beta cells, promotes glucose transport into skeletal muscle and adipose tissue as well as uptake of glucose by the liver for storage as glycogen. In Diabetes mellitus, insulin production and/or uptake is comprised and, consequently, blood glucose can elevate to abnormal concentrations ranging from 300 to 700 mg/100 ml. Excess insulin administration can cause severe hypoglycemia.
Although insulin deficiency can be ameliorated by treatment with diet, insulin or oral hypoglycemic agents, these standard modes of therapy have not been effective in preventing the development of chronic complications involving the eye, the kidney, the peripheral nervous system, and the peripheral arteries. Accurate determination of glucose levels in body fluids, such as blood, urine, and cerebro-spinal fluid, is a major aid in diagnosing and improving the therapeutic treatment of diabetes. It can reduce the long-term risk for developing coronary artery disease, visual impairment, renal failure, and peripheral vascular disease.
Colorimetric techniques have been developed to allow accurate self-determination of blood glucose levels by diabetic individuals. Although this method allows the patient to close the loop himself by altering the amount of insulin injected or the type and amount of food ingested, these methods are invasive and time consuming and they are especially bothersome for children. In order to overcome some of these limitations, several techniques have been proposed to continuously monitor glucose levels in the body, such as electrocatalysis.
However, there are major problems with the development of clinically useful continuous glucose sensors. In general, implanted sensors operate in the chemically and biologically harsh environment of the body for long periods of time. As such, they are subject to continuous fibrotic encapsulation and degradation which may raise questions about potential real-time responsiveness without significant delay, and the capability for integration with a pump.
Although implantation of an artificial endocrine pancreas and/or successful transplantation of islet tissue remain long range goals for improving the management of diabetes, the development of practical semi-invasive or non-invasive means for monitoring blood glucose levels could provide, if properly connected with an insulin pump through an appropriate controller, much of the potential benefit of these methods without the hazards of rejection and immunosuppression. Lastly, a noninvasive glucose sensor could have significant application in the diagnosis and management of Diabetes mellitis independently of the glucose pump controller applications.
An optical sensing approach using polarization rotation has been described by Rabinovitch, B., March, W. F., and Adams, R. L., in "Noninvasive Glucose Monitoring of the Aqueous Humor of the Eye; Part 1. Measurement of Very Small Optical Rotations", Diabetes Care, Vol. 5, No. 3; pp. 254-58, May-June 1982, and in "Noninvasive Glucose Monitoring of the Aqueous Humor of the Eye: Part II. Animal Studies and the Scleral Lens," Diabetes Care, Vol. 5, No. 3; pp. 259-65, May-June 1982. In their work it was found that measurement of glucose concentration in the aqueous humor of the eye correlated well with blood glucose levels with a minor time delay on the order of minutes. The glucose concentration in the aqueous humor was also found to be two orders of magnitude higher than any other optically active substances which were detected. A review of their work shows use of an amplitude measurement which is subject to a number of problems including noise susceptibility which limits the accuracy of the method.
The treatment of diabetes with prescribed injections of insulin subcutaneously results in inadequate control of glycemia compared to normal homeostatic control. Blood glucose levels rise and fall several times a day and, therefore, normoglycemia using an "open-loop" insulin delivery approach is difficult to maintain. An alternative solution to this problem would be to "close the loop" using a self-adapting insulin infusion device with a glucose biosensor which continuously detects the need for dispensing insulin at the correct rate and time.
There have been major advances in the development of reliable, versatile, and accurate insulin pumps. As mentioned, significant progress has also been made toward the development of various glucose sensors, particularly in terms of the electrocatalytic (Peura, R. A. and Mendelson, Y., "Blood Glucose Sensors: An Overview". IEEE/NSF Symposium on Biosensors: pp. 63-68, 1984; and Lewandowski, J. J., Malchesky, P. S., Zborowski, M., and Nose, Y., "Evaluation of a Miniature Blood Glucose Sensor", ASAIO Trans., 34(3); pp. 255-58, Jul.-Sep. 1988), electroenzymatic (Clark, L. C., and Noyes, L. K., "Theoretical and Practical Bases for Implantable Glucose Sensors with Special Reference to the Peritoneum", IEEE/NSF Symposium on Biosensors; pp. 69-74, 1984; Clark L. C. and Duggan, C. A., "Implanted Electroenzymatic Glucose Sensors", Diabetes Care, Vol. 5, No. 3, pp. 174-80, May-Jun. 1982), and various optical (Regnault, W. F., and Picciolo, G. L., "Review of Medical Biosensors and Associated Materials Problems:, J. Biomed Mater. Res., Applied Biomaterials Vol. 21, No. A2; pp. 163-80, 1987, - Rabinovitch, B., March, W. F., and Adams, R. L., "Noninvasive Glucose Monitoring of the Aqueous Humor of the Eye; Part 1. Measurement of Very Small Optical Rotations", Diabetes Care, Vol. 5, No. 3; pp. 254-58, May-Jun. 1982; and March, W. F., Rabinovitch, B., and Adams, R. L., "Noninvasive Glucose Monitoring of the Aqueous Humor of the Eye: Part II. Animal Studies and the Scleral Lens."Diabetes Care, Vol. 5, No. 3, pp. 259-65, May-Jun. 1982).
However, there remain major obstacles to the development of clinically useful continuous glucose sensors. According to the National Diabetes Advisory board, in the National Long-Range Plan to Combat Diabetes, "Without a question, the most important long-term advance yet to be made is the development of a continuous blood glucose sensor." The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDI) specifies that an ideal glucose sensor should include: "(a) accuracy and ability to distinguish blood glucose levels throughout the physiologic range; (b) real-time responsiveness without significant delay; (c) biocompatability and reliability for long periods: (d) small and easily implantable: (e) capability for integration with suitable pump system." (Department of Health and Human Services, Solicitation of the Public Health Service and the Health Care Financing Administration for Small Business Innovation Research (SBIR) Contract Proposals, PHS/HCFA 89-1, Due Date Dec. 9, 1988).
The principal object of the present invention is to provide a novel non-invasive optically based sensor for quantitative determination of optically active substances in a specimen.
It is also an object to provide such a sensor which exhibits a high degree of accuracy and which may be adapted for use with various types of specimens.
A specific object is to provide such a sensor which may be used for determination of glucose levels by measurement of the level in the aqueous humor.
A further object is to provide a novel and accurate non-invasive method for determination of the quantity of optically active substances in specimens.